Regorafenib: an evidence-based review of its potential in patients with advanced liver cancer

Abstract

Hepatocellular carcinoma (HCC) is the second-most common cause of cancer-related death in the world. In spite of HCC surveillance with repeated imaging, about 50% of patients are diagnosed at an advanced stage and are not amenable to curative treatment options. Sorafenib, a multikinase inhibitor, remains the standard of care for advanced HCC. Over the last 5 years, several other medications have been tested in Phase III trials. However, they have not shown any added benefit over sorafenib. Regorafenib, another multikinase inhibitor, has demonstrated inhibition of a broader range of kinases, along with higher inhibition potential in preclinical models. After its safety and pharmacological properties was studied in Phase I trials, a Phase II study evaluating the role of Regorafenib in patients with advanced HCC who progressed on sorafenib therapy demonstrated efficacy and a manageable safety profile. A Phase III trial is ongoing, and its result will help us better evaluate the role of Regorafenib in patients with advanced HCC.

Keywords: HCC; Regorafenib; advanced HCC; hepatocellular carcinoma; multikinase inhibitors.

Figure 1

Barcelona Clinic Liver Cancer staging system and treatment strategy. Note: Adapted from: This article was published in the Journal of Hepatology, 56, European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma, 908-943, Copyright Elsevier 2012. Abbreviations: RF, radiofrequency ablation; PEI, percutaneous ethanol injection; TACE, transcatheter arterial chemoembolization.

Figure 2

Pathways involved in the development of hepatocellular carcinoma. Note: Multikinase inhibitors sorafenib and Regorafenib activate growth receptors, oncogenes, and developmental Wnt pathway. Abbreviations: IGF, insulin-like growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; EGF, epidermal growth factor; FGF, fibroblast growth factor; PTEN, phosphatase and tensin homologue.

Figure 3

Structure of Regorafenib. 4-(4-[{(4-Chloro-3-[trifluoromethyl]phenyl) carbamoyl}amino]-3-fluorophenoxy)-N-methylpyridine-2-carboxamide.